ABSTRACT Manganese (Mn) is an essential metal, but elevated levels induce severe neurotoxicity that has no treatment. While the direct neurotoxic effects of Mn are well studied, Mn is predominantly excreted by the liver and intestines, and a high prevalence of neurotoxicity associated with elevated blood and brain Mn levels is reported in patients with liver disease. Moreover, recent epidemiological studies suggest that alterations in Mn excretory capacity are widely prevalent in the general population due to common genetic polymorphisms. Yet, the role of Mn excretion in modulating the outcomes of Mn induced neurological disease is unclear, and the critical question of whether the risk of Mn neurotoxicity depends on Mn excretion capacity has not been answered. Until recently, a major limitation in studying the relationship between Mn excretion and neurotoxicity was that the mechanisms of Mn excretion were unknown. Our recent work, supported by a NIEHS ?ONES? R01, revealed that the combined activities of two Mn transporters, SLC30A10 and SLC39A14, were necessary for Mn excretion ? SLC39A14 transported Mn from blood into the liver and intestines, and SLC30A10 excreted the intracellular Mn into bile and feces. Further, our analyses of Slc30a10 and/or Slc39a14 knockout mice demonstrated that brain Mn levels were primarily regulated by the excretory activities of these transporters in the liver and intestines. Based on the predominant role of excretion in controlling Mn levels in the brain, we hypothesize that hepatic and intestinal Mn excretion are critical modulators of the risks and outcomes of Mn neurotoxicity. We will test this hypothesis by leveraging liver or intestine specific Slc30a10 knockout or knockin mice, which we generated in the ONES phase, as novel human relevant models to decrease or increase Mn excretion, respectively. Aims 1 & 2 will directly establish the regulatory role of hepatic and intestinal Mn excretion in Mn neurotoxicity. In Aim 1, we will determine whether liver or intestine specific Slc30a10 knockout mice exhibit heightened sensitivity to Mn neurotoxicity. In Aim 2, we will test whether liver or intestine specific Slc30a10 knockin mice are protected against Mn neurotoxicity. Studies in Aim 2 have high translational relevance as they may identify increasing Mn excretion to be an effective strategy for the management of Mn neurotoxicity. Aim 3 will build on our finding that elevated Mn exposure enhanced SLC30A10 expression via Hif1? in the liver, providing a means to increase Mn excretion during toxicity. In Aim 3, we will elucidate the mechanisms and determine whether this response protects against neurotoxicity. These studies will provide foundational information about protective responses to Mn at the organism level, which have not yet been described, and set the stage to test if Hif1? activators, in clinical trials for other diseases, can be repurposed for Mn neurotoxicity. In sum, our studies will provide fundamental insights into a central, but overlooked, aspect of Mn neurotoxicity, and aid in the development of novel therapeutic approaches for Mn induced neurological disease.